title: The integrin coactivator kindlin-2 plays a critical role in angiogenesis in mice and zebrafish.
abstract: Kindlin-2, a widely distributed cytoskeletal protein, has been implicated in integrin activation, and its absence is embryonically lethal in mice and causes severe developmental defects in zebrafish. Knockdown of kindlin-2 levels in endothelial cells resulted in defective adhesive and migratory responses, suggesting that angiogenesis might be aberrant even with partial reduction of kindlin-2. This hypothesis has now been tested in the kindlin-2(+/-) mice. RM1 prostate tumors grown in kindlin-2(+/-) mice had fewer blood vessels, which were thinner and shorter and supported less tumor growth compared with wild-type littermates. The vessels that did form in the kindlin-2(+/-) mice lacked smooth muscle cells and pericytes and had thinner basement membranes, indicative of immature vessels. VEGF-induced angiogenesis in matrigel implants was also abnormal in the kindlin-2(+/-) mice. Vessels in the kindlin-2(+/-) mice were leaky, and BM transplantation from kindlin-2(+/-) to WT mice did not correct this defect. Endothelial cells derived from kindlin-2(+/-) mice had integrin expression levels similar to WT mice but reduced αVβ3-dependent signaling, migration, adhesion, spreading, and tube formation. Developmental angiogenesis was markedly impaired by kindlin-2 morpholinos in zebrafish. Taken together, kindlin-2 plays an important role in pathologic and developmental angiogenesis, which arises from defective activation of integrin αVβ3.
authors.affiliation: Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Pluskota
authors.forename: James J
authors.initials: JJ
authors.lastname: Dowling
authors.forename: Natalie
authors.initials: N
authors.lastname: Gordon
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Golden
authors.forename: Dorota
authors.initials: D
authors.lastname: Szpak
authors.forename: Xiaoxia Z
authors.initials: XZ
authors.lastname: West
authors.forename: Carla
authors.initials: C
authors.lastname: Nestor
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Ma
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bialkowska
authors.forename: Tatiana
authors.initials: T
authors.lastname: Byzova
authors.forename: Edward F
authors.initials: EF
authors.lastname: Plow
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D005260:Female; D055785:Gene Knockdown Techniques; D039302:Integrin alphaVbeta3 / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000503:physiopathology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: D003598:Cytoskeletal Proteins; D039302:Integrin alphaVbeta3; D020319:Oligodeoxyribonucleotides, Antisense; D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins